The overarching goal of this project is to accelerate the development and pre-clinical evaluation of new and effective approaches to therapy of hereditary retinal degenerations in man. These diseases are a major cause of human blindness, affecting ~200,000 Americans, and are caused by a large number mutations in over 200 retinally expressed genes, not all of which have yet been identified. Similar diseases also affect dogs, in many cases caused by similar gene mutations. In this project, studies will be undertaken using research colonies of dogs affected by such hereditary retinal diseases to better understand the genetic and pathogenetic mechanisms of the diseases, and evaluate potential methods of disease prevention, therapy or amelioration. Specific canine strains with well characterized retinal disorders will be maintained and bred at a centralized resource facility Mutant and age-matched control dogs will be made available to research investigators either for independent or collaborative studies aimed at understanding the molecular mechanisms involved in the diseases, and developing potential therapies that can be evaluated on a short- or long-term basis. In parallel, this centralized resource will be used by multiple investigators to accomplish the research goals of their own NIH funded grants. Lastly, hypothesis driven studies by the PI and collaborators will identify new patient-relevant retinal disease models, examine the cellular/molecular mechanisms resulting in photoreceptor cell death, survival or proliferation, and develop interventions that will modulate the diseases, and develop therapies targeted for late-stage retinal disease with an emphasis on promoter selection and combinatorial therapies adjunctive to gene augmentation. The proposed studies provide support for the principal hypothesis that collaborative research using these canine models, from a centralized well maintained resource colony, and with an experienced team of investigators will lead to critical proof of principle studies directed at developing safe and effective novel therapies for human retinal degenerations.